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Outrageous Price Charged for 17 alpha-hydroxyprogesterone caproate (17OHP): A Blessing in Disguise?

A recent New England Journal of Medicine commentator was shocked, shocked, to find that a drug company was price gouging. Joking aside, this is a particularly egregious example of Big Pharma behaving badly. After locking in the right to manufacture 17OHP, K-V Pharmaceutical Company raised the price of treating one pregnant woman at risk for preterm birth by virtue of a prior preterm birth from $300 to more than $29,000, limiting access, according to the commentary, to “the drug’s demonstrated clinical efficiency against a complication for which there are few effective preventive options.”

Why might this be a blessing in disguise? Earlier, I did a blog post, “Does Progesterone Treatment Prevent Preterm Birth? A Case of ‘Skim Milk Masquerades as Cream’”, questioning the effectiveness of progesterone in women with prior preterm birth, including a critique of the trial the commentary cites as demonstrating the effectiveness of intramuscular injections of 17OHP. In that trial, progesterone did not reduce the rate of preterm birth. The rate remained what it had been in similar women before the trial began. Instead, the rate in the control group was much higher than before, and that’s what created the difference between groups. Moreover, the rationale for progesterone is quieting the uterus, but it didn’t do that either. Just as many women in the progesterone group as the placebo group needed treatment for bouts of preterm contractions. Furthermore, another, bigger trial reported no difference in preterm birth rates. So much for “effective.” As I also pointed out in the earlier post, we have no data on the long-term effect of exposing fetuses to weeks of excessive levels of a sex hormone. True, exposure starts after sex organs have developed, but there is more to differentiating boys from girls than looking different, and it is mediated by an ongoing interplay of hormones. The new price barrier could, therefore, protect women and their babies from a treatment that probably doesn’t do them any good and might do their babies harm.

As for lack of preventive options, a social intervention holds great promise. A randomized controlled trial of group prenatal care by midwives (A.K.A. “Centering Pregnancy” ) was published in 2007 in Obstetrics and Gynecology—in other words, hardly buried in an obscure journal. Participants were 1000 women, most of whom were low-income black women, a group at high socioeconomic risk for preterm birth, who were assigned to either group prenatal care or standard care. The preterm birth rate was 14% in the standard care group versus 10% in the group prenatal care group, a one-third risk reduction after controlling for factors that increase risk of adverse perinatal outcomes. In African-American women, the reduction was even more striking: 16% versus 10%. Nothing, nothing anyone ever has tried has reduced preterm birth by a third in a general population.

Why would group prenatal care work? Because preterm delivery is strongly associated with chronic maternal stress. Group prenatal care builds community and helps women feel more competent and confident, as shown by the trial’s other positive outcomes: women in group sessions were less likely to have suboptimal prenatal care, knew more about pregnancy, felt better prepared for labor, were more likely to initiate breastfeeding, and were more satisfied with their prenatal care. With social interventions, everyone wins, not just women spared a preterm birth. Best of all, there is NO downside to group prenatal care, no worries about adverse effects of treatment short- or long-term. As has been said about doula care, another social intervention—which, BTW, is thought to work the same way to reduce cesareans by reducing fear and stress in labor—if group prenatal care were a drug, clinicians would have rushed to obtain it for every hospital pharmacy in the country. And you can bet that providing group prenatal care would cost a lot less than $30,000 per person and probably not even as much as $300, the cost of the cheap version of 17OHP.

Of course it is disappointing that 17OHP isn’t what it’s being cracked up to be. But social interventions have yet to be tried, and at the very least, as the 18th century French surveyor Cassini de Thury said,

 

“It is better to have absolutely no idea where one is than to believe confidently that one is where one is not.”

 

Posted by: Henci Goer

Doula Care, Evidence Based Medicine, Pre-term Birth, Science & Sensibility , , , , , , , , ,

  1. avatar
    Lamaze Educator
    March 30th, 2011 at 22:28 | #1

    Yes, Centering Pregnancy has that one study, but…
    I want to see more.
    Anecdotally, I’ve seen some pretty yucky things come from Centering. Some of the most difficult births I have been to have been with Centering families. And I will say that when I have families who are also doing Centering groups come into class, they know little more (if any more) than the other families. However, the care providers I work with think the Centering model is a replacement for prenatal education. I bet if you expand the groups that you look at, I doubt the benefits will be quite the same as the 2007 study. Bottom line? We need more info, because the main driving force I see right now is the ability to bill for many prenatal visits in the time you could take to do 1 or 2 quality appointments.

  2. March 30th, 2011 at 22:34 | #2

    Hi Henci –

    You are echoing something that has been said in the obstetrics community for some time, but in my opinion being a bit more definitive than is justified. A large randomized trial did show 17-OHP to be effective in preventing recurrent preterm birth. There has been a lot of speculation, as you know, about the high rate of preterm birth in the control group. We don’t know why that is, but I don’t think one can fairly say that the study showed no effectiveness. Other studies have shown effectiveness of other progestin formulations, such as the various Brazilian studies showing effectiveness of vaginal preparations in prevention of recurrent preterm birth.

    Does 17-OHP work? I don’t know. But since 17-OHP has been on the market, the rate of singleton preterm birth has decreased, despite a stable overall preterm birth rate. It certainly isn’t fair to say that the drug has no effectiveness with the level of certainty that you suggest.

    As for the effects of progestins on infants? There is data to suggest that it has a negative impact. As you mention, the drug isn’t started until well after organogenesis.

    I like the idea of group prenatal care, and would like to see it more widely used.

    Thanks!

  3. March 31st, 2011 at 08:51 | #3

    Wonderful to see Centering mentioned in this context, especially as there are so few evidence-based interventions available to providers to help reduce premature birth!

  4. March 31st, 2011 at 10:08 | #4

    @Lamaze Educator: For the sake of a furthered educational discussion, can you expand on your statement, “Some of the most difficult births I have been to have been with Centering families.”? What, in your estimation, made these births more difficult? Were the difficulties that occurred similar amongst several different births from Centering families, or all completely different? Is the ‘group prenatal care’ implicated here, or other factors such as the general health of the women or their socioeconomic/educational status of the women birthing that led to the difficulties? Did the births occur at the same facility or different locations? (Were there other factors I am not listing?)

    Thanks, in advance, for expanding on your comment and for furthering the dialog.

  5. March 31st, 2011 at 14:44 | #5

    @Nicholas Fogelson, MD
    If you read the earlier post on progesterone treatment, you will see that I summarized Dr. Keirse’s critique of the Brazilian trial, the only trial finding a reduction in preterm births. Nor did I take his word for it. I checked the accuracy of his criticisms. So what is the sum total of the evidence on effectiveness of progesterone treatment for preventing preterm birth in women with prior preterm birth?

    1) the Brazilian trial, a trial so flawed as to cast strong doubt on the validity of its conclusions;
    2) the trial discussed here and in the previous post that didn’t find that progesterone decreased preterm births but that the control group had an unexpectedly higher rate than the norm and a trial, moreover, that disconfirmed the rationale for progesterone use by finding similar numbers of women requiring treatment for preterm labor; and
    3)a third trial, the biggest trial of all, that didn’t find a difference in preterm birth rates.

    We obviously disagree, but I feel justified in asserting that progesterone treatment has not been shown to be effective in reducing preterm births in women with prior preterm birth. We have no well-conducted randomized controlled trials finding that it does and at least one well-conducted trial finding that it doesn’t.

    As for a decline in preterm births co-temporaneous with a rise in use of progesterone, years ago, Dr. Murray Enkin showed an audience of obstetricians that the rise in the use of cesarean and continuous EFM paralleled a decline in perinatal mortality. All nodded. He then proceeded to show that the decline was equally well correlated with the rise in crime in the U.K., the increasing number of televisions in that country, and the decline in the stork population of Holland. As much as it may make intuitive sense, the fact that two trends occur during the same time frame does not mean that one caused the other. In fact, the major strength of RCTs is that they *can* determine causality.

  6. avatar
    Nicole
    March 31st, 2011 at 15:11 | #6

    Lamaze Educator :
    Yes, Centering Pregnancy has that one study, but…
    I want to see more.
    Anecdotally, I’ve seen some pretty yucky things come from Centering. Some of the most difficult births I have been to have been with Centering families. And I will say that when I have families who are also doing Centering groups come into class, they know little more (if any more) than the other families. However, the care providers I work with think the Centering model is a replacement for prenatal education. I bet if you expand the groups that you look at, I doubt the benefits will be quite the same as the 2007 study. Bottom line? We need more info, because the main driving force I see right now is the ability to bill for many prenatal visits in the time you could take to do 1 or 2 quality appointments.

    I am both a Lamaze childbirth educator, and a Centering Facilitator. I would love to see a post all about Centering, as it is a powerful model of prenatal care and will have massive benefits for many women. However, I agree that a struggle we are having is that care providers think that Centering replaces prenatal classes. As an educator, I know that it SHOULD NOT replace, but rather complement, a good childbirth ed program. Now, I admit to being biased but I do believe that I work in one of the best childbirth ed programs in North America. I can see that Centering is better than nothing, and it is probably even better than poor childbirth ed, but it is certainly not better than the “Cadillac” childbirth ed we offer.

  7. March 31st, 2011 at 16:04 | #7

    @Henci Goer

    No doubt that the population correlation between 17-OHP and decreasing singleton preterm birth is just correlation, and does not preserve causation.

    I’m not some big 17-OHP thumper, but I think there is some evidence that it works, and some that it doesn’t. You say that the 2003 trial was not valid, but really have no criticism of its methodologies – only that you don’t like the way the control group came out. The trial you do like is methodologically sound in your opinion, though it really isn’t much different in methodology than the much larger trial published in 2003.

    Its another example of how evidence based medicine fails to answer our questions, and often falls to preconceived belief. Everyone attacks the methodology of the trials they don’t like the results of, and holds up the ones that are coincident with what they already believe. I do the same thing.

  8. March 31st, 2011 at 19:05 | #8

    @Nicholas Fogelson, MD
    I would add though, that it is entirely possible that the 2003 result was an alpha error, or “finding a difference between groups where there is none”. Most studies are powered with a 95% alpha, so 1 out of 20 trial executions a difference will be erroneously discovered. Given the other trials that were negative and the strange distribution of preterm births in the control group, it is certainly possible that this is what happened with this study.

  9. April 2nd, 2011 at 12:11 | #9

    That’s possible, of course, but I still find the more compelling data to be that the birth rate at < 37 weeks with progesterone treatment in the 2003 RCT was 36% compared with 37% in similar women before the study began, and the birth rate at < 37 weeks in the 2007 RCT was 42% in the progesterone treatment group compared with 41% in the placebo group. The similarity in preterm birth rates in the populations participating in the two trials supports that they can be viewed together, that is, there wasn't something different between the two populations that argues against combining them, and the agreement between them strengthens the evidence that progesterone treatment doesn't reduce preterm births in women with prior preterm births.

  10. April 2nd, 2011 at 12:18 | #10

    I’ll add, too, that the 2007 trial reported similar preterm birth rates at 35 weeks or less (23% progesterone vs. 27% placebo) and 32 weeks or less (10% progesterone vs. 11% placebo), so it doesn’t look like progesterone extended gestational length either, which would have been an important benefit even if it didn’t prevent births before 37 weeks.

  11. April 2nd, 2011 at 16:35 | #11

    It is a bit of a mystery. You’re not the only one with these questions about the 2003 study.

  12. avatar
    Allen
    April 3rd, 2011 at 18:50 | #12

    This is all very interesting information, but I am suffering from information overload, I think.
    My daughter had a difficult 1st pregnancy 2 months pre mature. She is at the end of her 1st trymester with #2 and is being advised to to start the 17a treatment. After reading the studies and seeing the Goer/fogelson debate here, we wont even mention the anecdotal evidence presented and it is, well, anecdotal, I am ready to throw up my hands and say don’t do anything as it can’t hurt you and it appears to not benifit either.
    The questions of organogenesis gives me concern also. Is there a study on ofspring who have been exposed to this treatment? Is there a study on centering that shows a positive/negative results?

  13. April 4th, 2011 at 20:31 | #13

    17OHP may not be effective for treating PTL but it was prescribed to me by a RE for low progesterone. I lost three pregnancies in a row before I was finally appropriately diagnosed. Someone may need this drug – if price gouging is illegial in other settings (crisis) then certainly it should be illegal here. Women who are at risk for losing their babies (at any point of the journey) feel like they are trying to stave off a crisis.

    Please look beyond this one narrow aspect of a drug’s prescribability. If a mom & doctor find this treatment appropriate, then the mom should be able to obtain this medicine without additional undue stress. No, the high price of this drug is not clearly a blessing.

  14. April 4th, 2011 at 21:06 | #14

    Someone may need this drug – if price gouging is illegial in other settings (crisis) then certainly it should be illegal here.

    Thank you for pointing out this slightly different indication for the drug’s use and for the appropriately emotional side of this issue: for women desperate to carry a pregnancy to term, the prospect of facing nearly $30k for a medication that might make that goal achievable for her is inexcusable, criminal and down-right greedy.

  15. April 5th, 2011 at 15:47 | #15

    @Allen
    I hear you and identify with you. The original post arose from my daughter’s experience. Membranes ruptured out of the blue at 32 w in her first pregnancy, and she gave birth at 33 w. When she became pregnant the second time, she was told that progesterone injections would begin at 20 w. Never having heard of this, she asked me to research it. The 2009 post (see link above) was the result. She decided against the injections. With the second baby, she had preterm labor of sufficient concern that she was hospitalized for a few days to treat it, but she was discharged, made it through, and he was born at 39 w. (This, BTW, is an example of the problem with anecdotal/observational evidence. Even with no treatment, the majority of women at risk for preterm birth will make it to term, which can make it appear that ineffective treatment worked, hence the critical need for well-designed and conducted trials in which women are randomly alloted to treatment or control group.)

    As for your question about follow-up in the children of treated women, as the earlier post discussed, we have follow-up on less than 200 children and then only up to age 4. That isn’t anything like enough children to detect uncommon, but clinically important, adverse effects, and it certainly isn’t long enough to determine whether progesterone treatment has any effects on reproductive function.

  16. April 5th, 2011 at 15:53 | #16

    @labortrials
    Good news! The FDA has decided to allow laboratories to continue making it. Someone sent me an article on this in the past few days, and I would include the link, but I’m not finding it easily.

  17. April 6th, 2011 at 13:40 | #17

    Here is a link to an article about the FDA approval of the lower priced drug: http://healthland.time.com/2011/03/30/fda-will-allow-cheaper-version-of-pregnancy-drug-to-be-sold/

  18. April 6th, 2011 at 21:31 | #18

    Thanks, Kimmelin!

  19. April 14th, 2011 at 18:40 | #19

    Yes that was very good news. It looks like Makena will be a total flop. Their stock has tanked and will likely dwindle to zero eventually

  20. avatar
    Adele
    June 28th, 2011 at 13:19 | #20

    Did they control for a prior abortion? A prior abortion significantly increases a mother’s risk for preterm birth.

  21. July 3rd, 2011 at 22:41 | #21

    They didn’t, but they didn’t need to. These were randomized controlled trials. One of strengths of RCTs is that assigning participants to one group or the other by chance(random allocation) results in known (and unknown) factors that might affect outcomes being evenly distributed.

  1. April 18th, 2011 at 11:48 | #1